One in every ten thousand people in the USA has Huntington's disease, and it impacts many more. Multiple generations within a family can inherit the disease, resulting in escalating health care costs and draining family resources. This highly devastating and fatal disease touches all races and socioeconomic levels, and there are currently no cures. Screening for the mutant HD gene is available, but the at-risk children of an affected parent often do not wish to be tested since there are currently no early prevention strategies or effective treatments.

We propose a novel therapy to treat HD; implantation of cells engineered to secrete Brain-Derived Neurotrophic factor (BDNF), a factor needed by neurons to remain alive and healthy, but which plummets to very low levels in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease. Intrastriatal implantation of mesenchymal stem cells (MSC) has significant neurorestorative effects and is safe in animal models. We have discovered that MSC are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into each damaged cell that they contact. Thus we are utilizing nature's own paramedic system, but we are arming them with enhanced neurotrophic factor secretion to enhance the health of at-risk neurons. Our novel animal models will allow the therapy to be carefully tested in preparation for a phase 1 clinical trial of MSC/BDNF infusion into the brain tissue of HD patients, with the goal of restoring the health of neurons that have been damaged by the mutant htt protein.

Delivery of BDNF by MSC into the brains of HD mice is safe and has resulted in a significant reduction in their behavioral deficits, nearly back to normal levels. We are doing further work to ensure that the proposed therapy will be safe and effective, in preparation for the phase 1 clinical trial.

The significance of our studies is very high because there are currently no treatments to diminish the unrelenting decline in the numbers of medium spiny neurons in the striata of patients affected by HD. However this biological delivery system for BDNF could also be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1), Alzheimer's Disease, and some forms of Parkinson's Disease, where neuroregeneration is needed. Development of novel stem cell therapies is extremely important for the community of HD and neurodegenerative disease researchers, patients, and families. Since HD patients unfortunately have few other options, the benefit to risk ratio for the planned trial is very high.

Statement of Benefit to California:

It is estimated that one in 10,000 CA residents have Huntington’s disease (HD). While the financial burden of HD is estimated to be in the billions, the emotional cost to friends, families, and those with or at risk for HD is immeasurable. Health care costs are extremely high for HD patients due to the long progression of the disease, often for two decades. The lost ability of HD patients to remain in the CA workforce, to support their families, and to pay taxes causes additional financial strain on the state’s economy. HD is inherited as an autosomal dominant trait, which means that 50% of the children of an HD patient will inherit the disease and will in turn pass it on to 50% of their children. Individuals diagnosed through genetic testing are at risk of losing insurance coverage in spite of reforms, and can be discriminated against for jobs, school, loans, or other applications. Since there are currently no cures or successful clinical trials to treat HD, many who are at risk are very reluctant to be tested. We are designing trials to treat HD through rescuing neurons in the earlier phases of the disease, before lives are devastated.

Mesenchymal stem cells (MSC) have been shown to have significant effects on restoring synaptic connections between damaged neurons, promoting neurite outgrowth, secreting anti-apoptotic factors in the brain, and regulating inflammation. In addition to many trials that have assessed the safety and efficacy of human MSC delivery to tissues via systemic IV infusion, MSC are also under consideration for treatment of disorders in the CNS, although few MSC clinical trials have started so far with direct delivery to brain or spinal cord tissue. Therefore we are conducting detailed studies in support of clinical trials that will feature MSC implantation into the brain, to deliver the neurotrophic factor BDNF that is lacking in HD. MSC can be transferred from one donor to the next without tissue matching because they shelter themselves from the immune system. We have demonstrated the safe and effective production of engineered molecules from human MSC for at least 18 months, in pre-clinical animal studies, and have shown with our collaborators that delivery of BDNF can have significant effects on reducing disease progression in HD rodent models.

We are developing a therapeutic strategy to treat HD, since the need is so acute. HD patient advocates are admirably among the most vocal in California about their desire for CIRM-funded cures, attending almost every public meeting of the governing board of the California Institute for Regenerative Medicine (CIRM). We are working carefully and intensely toward the first FDA-approved approved cellular therapy for HD patients which could have a major impact on those affected in California. In addition, the methods, preclinical testing models, and clincial trial design that we are developing could have far-reaching impact on the treatment of other neurodegenerative disorders.

Progress Report:

A) Pre-clinical: The remainder of the IND-enabling studies were designed in consultation with Biologics Consulting Group (BCG). The project will begin with the IND-enabling phase and transition through regulatory approvals and through an observational trial and the Phase I clinical trial of stem cell therapy. The project has a Preclinical unit, under the leadership of co-PI Dr. Jan Nolta, and a Clinical unit, under the leadership of PI Dr. Vicki Wheelock. The two units are well integrated, since the team has been meeting weekly since 2009 to plan the testing of MSC trials for HD. During the planning phase we had a minimum of 4 hours of HD meetings per week, and worked continually on the project. This team is truly translational, with both PIs highly dedicated to this trial and motivated by the HD community.

Co-PI Jan Nolta, Ph.D. is Scientific Director of the UC Davis/CIRM GMP Facility, and will continue to direct ongoing IND-enabling studies for MSC/BDNF. The Pre-Clinical team will perform all IND-enabling studies at the level of GLP, and will manufacture and qualify the MSC and MSC/BDNF products in the GMP facility at UC Davis that is directed by Dr. Bauer (CMC lead). These studies are ongoing and we have been advised by BCG consulting lead Andra Miller, who was formerly Gene Therapy Group Leader at the FDA, CBER, Division of Cell and Gene Therapies, for almost a decade. BCG is assisting us with IND preparation.
Ms. Geralyn Annett is the experienced Project Manager. She is the UCD Stem Cell Program Manager and has worked in the field of academic and industry stem cell trials for 20+ years. She will oversee the regulatory team and keep the IND-enabling studies on task to meet the milestones. GMP Facility Director Gerhard Bauer will be responsible for regulatory filings with assistance from Dr. Nolta, the CMC team, and Dr. Miller. Dr. Nolta has worked on clinical trials of stem cell gene therapy, and associated translational studies with Ms. Annett and Director Bauer for over 20 years.
B) Clinical. The Clinical team is led by PI Dr. Vicki Wheelock, who is Director of the HDSA Center of Excellence at UC Davis and, with nurse practitioner Terry Tempkin, follows over 250 patients with HD in the UC Davis Movement Disorders clinic. The PI has extensive experience in conducting clinical trials and has already accrued HD patients to 14 clinical trials to date. The planning grant allowed us to conduct longer weekly meetings with different team members to complete planning of the proposed clinical trial.

Weekly HD meetings during the planning phase included PI Dr. Wheelock, Co-PI Dr. Nolta, Nurse practitioner Terry Tempkin, Program Manager Geralyn Annett, Psychiatrist Dr. Lorin Scher, Neuropsychologist Dr. Sarah Farias, Social Worker Lisa Kjer, and members of the Imaging Unit led by Dr. Charles DeCarli. This team has worked together on multiple clinical trials for HD patients. Some meetings additionally included Dr. Kiarash Shahlaie, the UCD functional neurosurgeon who will perform the targeting and surgical implantation of the cells, Dr. Bauer who directs the GMP facility (and his team members), the translational team who is performing the IND-enabling studies in Rodents (they usually meet separately for 2 hours/week with Dr. Nolta), and Dr. Tarantal who is leading the IND-enabling studies in non-human primates.
We met with our CRO, Paragon, who will be responsible for regulatory and safety filings including outcomes reports, medical and safety monitoring and management including DSMB, medical writing and quality assurance, clinical events committee- adjudicate AEs, and generate clinical study reports. Paragon will also oversee the development of the electronic case report forms, site management and monitoring, biostatistical analysis, and management of the database. We had on-site meetings and conference calls with Paragon during the planning Phase.
Additional meetings were conducted with collaborators and consultants:
A) Dunbar lab and Hersch lab in the US, both leaders in the HD field – for HD trial IND-enabling study research and HD mouse and patient biomarkers, respectively.
B) Aylward lab in the US for detailed brain imaging analyses in HD.
C) Paulsen lab for interpretation of cognitive assays in HD.
D) Phil Starr and Dan Lim at UCSF for ClearPoint cell injection system.
E) Bachoud-Levi lab in France for cell implantation in HD.
F) Dr. Robert (Willie) Mays and Bob Deans, Athersys – for IND-enabling studies/regulatory
In conclusion, the planning grant helped us to finalize plans for the proposed clinical trial and to complete our detailed plans for the remainder of the IND-enabling studies required to obtain FDA approval. These goals were accomplished through frequent meetings with key consultants and collaborators during the intense planning phase, where we completed the Disease Team application to CIRM that could potentially fund our proposed Phase I clinical trial of MSC/BDNF therapy for Huntington’s disease.